Compositions and methods of treating muscle dystrophy

Patent metadata

Field	Value
Publication number	US-2025381285-A1
Application number	US-202519263325-A
Country	US
Kind code	A1
Filing date	Jul 8, 2025
Priority date	Mar 27, 2020
Publication date	Dec 18, 2025
Grant date	—

Abstract

Disclosed herein are polynucleic acid molecules, pharmaceutical compositions, and methods for treating muscle dystrophy (DM1).

First claim

What is claimed is:

1 . A conjugate comprising (i) an anti-transferrin receptor antibody or antigen binding fragment thereof, (ii) an siRNA molecule, which comprises a guide strand and a passenger strand, and (iii) a linker;
wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises a variable heavy chain (VH) region, which comprises an HCDR1 comprising the sequence of SEQ ID NO: 17; an HCDR2 comprising the sequence of SEQ ID NO: 20; and an HCDR3 comprising the sequence of SEQ ID NO: 19; wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises a variable light chain (VL) region, which comprises a LCDR1 comprising the sequence of SEQ ID NO: 22; a LCDR2 comprising the sequence of SEQ ID NO: 23; and a LCDR3 comprising the sequence of SEQ ID NO: 24; and wherein the passenger strand of the siRNA comprises the sequence of SEQ ID NO: 3 and the guide strand of the siRNA comprises the sequence of SEQ ID NO: 4; and wherein the linker comprises a maleimide group that conjugates the anti-transferrin receptor antibody or antigen binding fragment thereof to a terminus of the guide strand or the passenger strand.

2 . The conjugate of claim 1 , wherein the maleimide group is selected from the group consisting of succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) and sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-sMCC).

3 . The conjugate of claim 1 , wherein the linker conjugates the anti-transferrin receptor antibody or antigen binding fragment thereof to a 5′ end terminus of the passenger strand.

4 . The conjugate of claim 1 , wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is a full-length anti-transferrin receptor antibody.

5 . The conjugate of claim 4 , wherein the full-length anti-transferrin receptor antibody is a humanized anti-transferrin receptor antibody or a human anti-transferrin receptor antibody.

6 . The conjugate of claim 4 , wherein the full-length anti-transferrin receptor antibody further comprises a mutation in the heavy chain constant region selected from the group consisting of L233A, L234A, and L327R.

7 . The conjugate of claim 4 , wherein the full-length anti-transferrin receptor antibody further comprises a mutation in the heavy chain constant region selected from the group consisting of L233A, L234A, and L327R.

8 . The conjugate of claim 1 , wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is selected from the group consisting of monovalent Fab′, divalent Fab2, and single chain variable fragment (scFv).

9 . A conjugate comprising (i) an anti-transferrin receptor antibody or antigen binding fragment thereof, (ii) an siRNA, which comprises a guide strand and a passenger strand, and (iii) a linker;
wherein the anti-transferrin receptor antibody or antigen binding fragment thereof comprises the variable heavy chain (VH) sequence of SEQ ID NO: 30 and the variable light chain (VL) sequence of SEQ ID NO: 34; wherein the passenger strand of the siRNA comprises the sequence of SEQ ID NO: 3 and the guide strand of the siRNA comprises the sequence of SEQ ID NO: 4; and wherein the linker comprises a maleimide group that conjugates the anti-transferrin receptor antibody or antigen binding fragment thereof to a terminus of the guide strand or the passenger strand.

10 . The conjugate of claim 9 , wherein the maleimide group is selected from the group consisting of succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) and sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-sMCC).

11 . The conjugate of claim 9 , wherein the linker conjugates the anti-transferrin receptor antibody or antigen binding fragment thereof to a 5′ end of the passenger strand.

12 . The conjugate of claim 9 , wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is a full-length anti-transferrin receptor antibody.

13 . The conjugate of claim 12 , wherein the full-length anti-transferrin receptor antibody is a humanized anti-transferrin receptor antibody or a human anti-transferrin receptor antibody.

14 . The conjugate of claim 12 , wherein the full-length anti-transferrin receptor antibody further comprises a mutation in the heavy chain constant region selected from the group consisting of L233A, L234A, and L327R.

15 . The conjugate of claim 12 , wherein the full-length anti-transferrin receptor antibody further comprises the L233A, L234A and L327R mutations in the heavy chain constant region.

16 . The conjugate of claim 9 , wherein the anti-transferrin receptor antibody or antigen binding fragment thereof is selected from the group consisting of monovalent Fab′, divalent Fab2, and single chain variable fragment (scFv).

17 . A conjugate comprising (i) an anti-transferrin receptor antibody, (ii) an siRNA molecule, which comprises a guide strand and a passenger strand, and (iii) a linker;
wherein the anti-transferrin receptor antibody comprises two heavy chains, each of which comprises SEQ ID NO:48, and two light chains, each of which comprises SEQ ID NO:63; wherein the passenger strand of the siRNA comprises the sequence of SEQ ID NO: 3 and the guide strand of the siRNA comprises the sequence of SEQ ID NO: 4; and wherein the linker comprises a maleimide group that conjugates the anti-transferrin receptor antibody to a 5′ end terminus of the passenger strand of the siRNA.

18 . The conjugate of claim 17 , wherein the maleimide group is selected from the group consisting of succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) and sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-sMCC).

Assignees

• Avidity Biosciences Inc

Inventors

• Doppalapudi Venkata Ramana
• Hood Michael David
• Burke Rob
• COCHRAN Michael Caramian
• Darimont Beatrice Diana
• Shi Yunyu
• Marelius Gulin Erdogan
• Malecova Barbora

Classifications

• C12N2310/3521

  Methyl · CPC title

• C07K16/28

  against receptors, cell surface antigens or cell surface determinants · CPC title

• C12N2310/3533

  Halogen · CPC title

• C07K16/2881

  against CD71 · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title